Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
Clin Cancer Res. 2022 Oct 3;28(19):4248-4257. doi: 10.1158/1078-0432.CCR-22-1152.
Modified gemcitabine and S-1 (GS) is an active regimen for patients with advanced biliary tract cancer (ABTC) in our previous study. Herein, we report the results of a single-arm phase II of nivolumab plus modified GS (NGS) as first-line treatment in ABTC.
Patients received nivolumab 240 mg and 800 mg/m2 gemcitabine on day 1 plus daily 80/100/120 mg of S-1 (based on body surface area) on days 1 to 10, in a 2-week cycle. The primary endpoint was the objective response rate (ORR). The correlation between therapeutic efficacy and genetic alterations with signatures identified by targeted next-generation sequencing panels was explored.
Between December 2019 and December 2020, 48 eligible patients were enrolled. After a median of 17.6 months of follow-up, the ORR was 45.9% [95% confidence interval (CI), 31.4%-60.8%]. The median progression-free survival (PFS) and overall survival (OS) was 9.1 (95% CI, 5.8-9.6) and 19.2 (95% CI, 11.6-not reached) months, respectively. All grade 3/4 treatment-related adverse events (AE) were less than 10%, except fatigue (14.6%) and skin rash (10.4%). Eighteen patients (35.4%) experienced immune-related AEs without treatment-related death. High tumor mutational burden (TMB-H; top 20%; ≥7.1 mut/Mb) only predicted prolonged median PFS but not OS. Up to 28.9% of patients who harbored loss-of-function mutations in chromatin remodeling genes demonstrated significantly longer median PFS and OS than those without alterations.
NGS is a safe and promising regimen in ABTC. Impaired functions of chromatin remodeling genes may be a potential surrogate biomarker with predictive value in this study.
在我们之前的研究中，改良吉西他滨和 S-1（GS）是晚期胆道癌（ABTC）患者的有效方案。在此，我们报告了nivolumab 联合改良 GS（NGS）作为 ABTC 一线治疗的单臂 II 期临床试验结果。
患者接受 nivolumab 240mg 和 800mg/m2 吉西他滨，于第 1 天，每日 100/120mg S-1（基于体表面积），于第 1 至 10 天，每 2 周为一个周期。主要终点是客观缓解率（ORR）。探索了治疗疗效与通过靶向下一代测序面板确定的特征之间的遗传改变的相关性。
2019 年 12 月至 2020 年 12 月，共纳入 48 例符合条件的患者。中位随访 17.6 个月后，ORR 为 45.9%（95%CI，31.4%-60.8%）。中位无进展生存期（PFS）和总生存期（OS）分别为 9.1（95%CI，5.8-9.6）和 19.2（95%CI，11.6-未达到）个月。所有 3/4 级治疗相关不良事件（AE）均小于 10%，除疲劳（14.6%）和皮疹（10.4%）。18 例（35.4%）患者发生免疫相关 AE，无治疗相关死亡。高肿瘤突变负荷（TMB-H；前 20%；≥7.1 mut/Mb）仅预测中位 PFS 延长，但不预测 OS。高达 28.9%携带染色质重塑基因功能丧失突变的患者的中位 PFS 和 OS 明显长于无改变的患者。
NGS 是 ABTC 安全且有前景的方案。在这项研究中，染色质重塑基因功能障碍可能是具有预测价值的潜在替代生物标志物。
